The proposed research has been directed toward elucidating the role of the liver in the physiological disposition of insulin and possible derangements in diabetes. To these ends the effect of factors which have been reported to influence the degradation of insulin by the liver, such as starvation and experimentally-induced diabetes, are being investigated in the rat with respect to plasma clearance of 125I insulin, uptake, and degradation in selected organs and tissues and appearance of degraded products in plasma. Furthermore the subcellular distribution and degradation of the labeled hormone and related peptides as a function of time following intraportal injection are being studied and the interrelationship between membrane binding, biological activity and degradation are being investigated. Studies have been planned on the kinetics of plasma clearance and appearance of degraded products in plasma of intravenously-injected labeled insulin in non-obese normals under various physiological conditions, in obese individuals, and diabetic patients. On the basis of the disposition studies in the rats thus far, it would be possible to detect derangements in the disposition of insulin, the nature of the derangement and the role of the liver in their causation.